Molecular genetics of Pompe disease: a comprehensive overview

Peruzzo, Paolo; Pavan, Eleonora; Dardis, Andrea

doi:10.21037/atm.2019.04.13

Cited by 58 publications

(57 citation statements)

References 79 publications

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“…To date, over 500 pathogenic (P) or likely pathogenic (LP) variants and numerous benign variants and variants of unknown significance (VUS) in the GAA gene have been reported (ClinVar, 2017; Erasmus MC University Medical Center, 2017; Aggregation Databases (ExAC, gnomAD), 2017; Leiden Open Variation Database (LOVD), 2018; The Human Genome Mutation Database (HGMD), 2017). A review of GAA variants suggests that missense variants are the most frequent molecular genetic cause of PD (~50%), followed by small deletions [8,15]. Variant hotspots are also known, such as the c.-32-13T>G splice site single nucleotide variant and the exon 18 deletion (c.2481+102_2646+31del).…”

Section: The Variant Spectrum Of Pompe Diseasementioning

confidence: 99%

“…Variant hotspots are also known, such as the c.-32-13T>G splice site single nucleotide variant and the exon 18 deletion (c.2481+102_2646+31del). These and other ethnic variants are well described [8,15], but require detection by DNA sequencing methods that can identify both single nucleotide variations (SNVs), as well as copy number variations (CNVs, also known as deletion/duplication events), and these are discussed later.…”

Section: The Variant Spectrum Of Pompe Diseasementioning

confidence: 99%

“…These topics have been well covered by other reviews [8,15], and therefore only discussed in the context of second tier testing algorithm for PD NBS (Figure 2). In PD, the genotype is generally fully penetrant; IOPD phenotypes especially demonstrate limited heterogeneity.…”

Section: Prediction Of Genotype-phenotype Effectsmentioning

confidence: 99%

“…Due to the fact that CNV events such as those reported in GAA exon 18 [8,15] and other heterogeneous CNVs comprise a significant fraction of pathogenic PD variants, a PD NBS second tier tNGS assay must integrate detection of CNV events. While data from targeted small gene panels are scarce, recent reports of PD whole exome sequences provide insight into CNVs.…”

Section: Copy Number Variation (Cnv) and False Negative Riskmentioning

confidence: 99%

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Second Tier Molecular Genetic Testing in Newborn Screening for Pompe Disease: Landscape and Challenges

Smith

Bainbridge

Parad

et al. 2020

IJNS

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Pompe disease (PD) is screened by a two tier newborn screening (NBS) algorithm, the first tier of which is an enzymatic assay performed on newborn dried blood spots (DBS). As first tier enzymatic screening tests have false positive results, an immediate second tier test on the same sample is critical in resolving newborn health status. Two methodologies have been proposed for second tier testing: (a) measurement of enzymatic activities such as of Creatine/Creatinine over alpha-glucosidase ratio, and (b) DNA sequencing (a molecular genetics approach), such as targeted next generation sequencing. (tNGS). In this review, we discuss the tNGS approach, as well as the challenges in providing second tier screening and follow-up care. While tNGS can predict genotype-phenotype effects when known, these advantages may be diminished when the variants are novel, of unknown significance or not discoverable by current test methodologies. Due to the fact that criticisms of screening algorithms that utilize tNGS are based on perceived complexities, including variant detection and interpretation, we clarify the actual limitations and present the rationale that supports optimizing a molecular genetic testing approach with tNGS. Second tier tNGS can benefit clinical decision-making through the use of the initial NBS DBS punch and rapid turn-around time methodology for tNGS, that includes copy number variant analysis, variant effect prediction, and variant ‘cut-off’ tools for the reduction of false positive results. The availability of DNA sequence data will contribute to the improved understanding of genotype-phenotype associations and application of treatment. The ultimate goal of second tier testing should enable the earliest possible diagnosis for the earliest initiation of the most effective clinical interventions in infants with PD.

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Section: The Variant Spectrum Of Pompe Diseasementioning

confidence: 99%

Section: The Variant Spectrum Of Pompe Diseasementioning

confidence: 99%

Section: Prediction Of Genotype-phenotype Effectsmentioning

confidence: 99%

Section: Copy Number Variation (Cnv) and False Negative Riskmentioning

confidence: 99%

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Second Tier Molecular Genetic Testing in Newborn Screening for Pompe Disease: Landscape and Challenges

Smith

Bainbridge

Parad

et al. 2020

IJNS

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“…El análisis de la secuencia genomica podría detectar del 83 al 93% de la proporción de probandos con variantes patogénicas, mientras que el análisis de deleción/ duplicación dirigida a genes solo detecta de 5 a 13%. [11][12][13] La información del gen está codificado como ORPHA 420429 en Orphanet; en CIE-10 con E74.0; en UMLS: C3888925; y en MIM 232300. La mutación se ubica en el segmento 17q25.3, y el número de fenotipo MIM es 232300; la clave de mapeo de fenotipo es 3; el gen/locus es GAA, y el número MIM del gen es 606800.…”

Section: Introductionunclassified

Enfermedad de Pompe de inicio tardío desencadenada por el embarazo, reporte de una variante clínica genómica descrita por primera vez en un adulto.

2020

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Antecedentes: esta es la primera vez en el mundo que la variante NM_000152 (GAA_V001): c.1555A˃G; p. (Met519Val), se describe en una mujer adulta, desencadenada por el embarazo. Es una mutación sin sentido por sustitución, homocigótica, probablemente patógena. Reporte del caso: se trata de una mujer adulta mestiza, nacida y residente en Ecuador, que durante su período de lactancia, después de un embarazo y un parto por cesárea, debutó con un trastorno musculoesquelético. Se hospitalizó a la paciente en el Hospital Eugenio Espejo en Quito, Ecuador; donde ella ha sido readmitida por varias veces. Los hallazgos clínicos más relevantes fueron debilidad muscular proximal, debilidad muscular de las extremidades inferiores, dificultad para subir escaleras, insuficiencia respiratoria debido a debilidad muscular, edema de las extremidades inferiores, deterioro de las actividades de la vida diaria, ortopnea, trastornos del sueño y debilidad muscular. Además, encontró niveles elevados de creatina quinasa sérica, actividad enzimática y coenzima anormal, escoliosis lumbar, hipertensión arterial pulmonar, con regurgitación tricuspídea y regurgitación mitral leve, reemplazo graso del músculo esquelético, insuficiencia pulmonar, miopatía esquelética y descargas miotónicas en EMG. Conclusión: esta es la primera vez en el mundo que la variante NM_000152 (GAA_V001): c.1555A˃G; p. (Met519Val), la sustitución por una mutación sin sentido, homocigota, probablemente patógena se describe en un adulto. Es el primer caso desencadenado por el embarazo, el primer caso de inicio tardío descrito en Ecuador y el primer caso descrito en una mujer mestiza de Ecuador.

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Classic infantile‐onset Pompe disease with histopathological neurologic findings linked to a novel GAA gene 4 bp deletion: A case study

Cerón‐Rodríguez

Castillo‐García

Acosta‐Rodríguez‐Bueno

et al. 2022

Molec Gen & Gen Med

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Pompe disease (PD) is an autosomal recessive disorder by a deficiency of acid α‐glucosidase (GAA) with intralysosomal glycogen accumulation in multiple tissues. We present the case of a 5‐month‐old male with hypertrophic cardiomyopathy, hypotony, feeding difficulties, and oxygen requirement since birth. At 3 months of age, he develops heart failure, respiratory impairment, and neurological deterioration. The echocardiogram revealed concentric hypertrophic cardiomyopathy with left‐diastolic dysfunction. We found increased creatine‐phosphokinase, lactate dehydrogenase, and urinary glucose tetrasaccharide levels, 50% of PAS‐positive vacuolated lymphocytes in the peripheral blood smear, and low GAA activity. Sequencing of coding exons and flanking intronic sequences revealed a novel homozygous 4 bp deletion in exon 15 of the GAA gene (c.2066_2069delAGCC/p.Glu689Glyfs*6). IOPD was diagnosed. At 5 months old, we started enzyme replacement therapy with an alpha‐alglucosidase of 20 mg/kg weekly and immunomodulation with intravenous immunoglobulin. He developed two cardiorespiratory arrests with subsequent neurologic deterioration, convulsive crisis, and respiratory failure and died at 9 months old. We found the usual PD hallmarks in the heart, striated muscle, and liver but also we found neuronal lesions characterized by cytoplasm vacuolization with PAS‐positive granules in the central nervous system and myenteric plexus. We describe a novel GAA gene pathogenic variant with a particular phenotype characterized by classic IOPD and neurologic histopathological findings. Enhancing the knowledge of lysosomal diseases is critical to improving the diagnosis and treatment of these patients.

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Molecular genetics of Pompe disease: a comprehensive overview

Cited by 58 publications

References 79 publications

Second Tier Molecular Genetic Testing in Newborn Screening for Pompe Disease: Landscape and Challenges

Second Tier Molecular Genetic Testing in Newborn Screening for Pompe Disease: Landscape and Challenges

Enfermedad de Pompe de inicio tardío desencadenada por el embarazo, reporte de una variante clínica genómica descrita por primera vez en un adulto.

Classic infantile‐onset Pompe disease with histopathological neurologic findings linked to a novel GAA gene 4 bp deletion: A case study

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